Metabolism of the Carbocyclic Nucleoside Analogue Carbovir, an Inhibitor of Human Immunodeficiency Virus, in Human Lymphoid Cells

Laureano L. Bondoc, Arnold Fridland, William M. Shannon, John A. Secrist, Robert Vince

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Carbovir (CBV) is a highly selective carbocyclic nucleoside inhibitor of HIV replication in human lymphocytes and is potentially useful in the treatment of AIDS [Vince et al. (1988) Biochem. Biophys. Res. Commun. 156, 1046-1053]. Using human lymphoid cells severely deficient in nucleoside kinases, we were able to identify the route of activation of CBV metabolism. The present studies have demonstrated that CBV is anabolized to the mono-, di-, and triphosphates and to guanosine 5′-triphosphate in CCRF-CEM cells. Conversion to GTP amounted to 15-20% of the total analogue nucleotides formed in the cells and may arise from CBV through depurination and salvage via HGPRT. Evidence was obtained that neither deoxycytidine kinase, adenosine kinase, or mitochondrial deoxyguanosine kinase is primarily involved in the initial step of phosphorylation of CBV in CCRF-CEM cells. In contrast, earlier studies [Johnson & Fridland (1989) Mol. Pharmacol. 36, 291-295] showed that a cytosolic 5′-nucleotidase catalyzes the activation of CBV to the monosphosphate. Other biochemical effects examined showed that the nucleobases hypoxanthine and adenine, but not guanine, their respective nucleosides, and the dideoxynucleosides 2′,3′-di-deoxyinosine, 2′,3′-dideoxyguanosine, and 3′-azido-3′-deoxythymidine produced significant increased accumulation of CBV nucleotides in CEM cells. The exact mechanism for this potentiation of CBV phosphorylation has not been elucidated but may be due to a modulating effect of intracellular nucleotides on 5′-nucleotidase activity.

Original languageEnglish (US)
Pages (from-to)9839-9843
Number of pages5
JournalBiochemistry
Volume29
Issue number42
DOIs
StatePublished - Oct 1 1990

Fingerprint Dive into the research topics of 'Metabolism of the Carbocyclic Nucleoside Analogue Carbovir, an Inhibitor of Human Immunodeficiency Virus, in Human Lymphoid Cells'. Together they form a unique fingerprint.

Cite this